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Clin Cancer Res. 2018 Sep 15;24(18):4399-4406. doi: 10.1158/1078-0432.CCR-18-0481. Epub 2018 May 30.

Phase I Trials of Anti-ENPP3 Antibody-Drug Conjugates in Advanced Refractory Renal Cell Carcinomas.

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Division of Medical Oncology, University of Washington, Seattle, Washington.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York.
Harvard Medical School, Dana-Farber Cancer Institute, Boston, Massachusetts.
Division of Hematology/Oncology, Karmanos Cancer Center, Detroit, Michigan.
Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan.
Cross Cancer Institute, Edmonton, Alberta, Canada.
London Health Sciences Centre, London, Ontario, Canada.
Department of Oncology, Indiana University, Bloomington, Indiana.
Department of Opthalmology and Visual Science, University of Texas McGovern Medical School, Houston, Texas.
Department of Translational Research, Agensys, Inc. Santa Monica, California.
Astellas Pharma, Northbrook, Illinois.
BC Cancer, Vancouver Centre, Vancouver, British Columbia, Canada.


Purpose: To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody-drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC).Patients and Methods: Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary-derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks.Results: The AGS-16M8F study (n = 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7-83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study (n = 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100-143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control >37 weeks (37.5-141 weeks).Conclusions: AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks. Clin Cancer Res; 24(18); 4399-406. ©2018 AACR.

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